The overall objective of this proposal is to carry out a systematic investigation of the pharmacokinetics and pharmacodynamic effects of methadone, acetylmethadol, morphine and heroin in the maternal-fetal unit. The studies will be carried out using the chronic pregnant ewe animal model. The study will be divided into two phases. Phase I will involve the study of the distribution and elimination of the drug and metabolites in the mother and fetus after acute administration. The effects of acute drug administration on maternal and fetal blood gases, blood pressure, heart rate, uterine and umbilical blood flow, and substrate uptake and utilization by the fetus will be determined. The effects of acute drug administration on fetal brain function (EEG) and fetal movements will also be studied. Phase II will involve chronic administration of the drug during the third trimester with intermittent blood sampling in order to determine the distribution and accumulation of the drug and metabolites in mother and fetus. The effects of chronic drug administration on fetal growth and development will be examined. An understanding of the pharmacokinetics and pharmacodynamic actions of the drug in the maternal-fetal unit may lead to a better understanding of the mechanisms by which these drugs affect fetal growth and development.